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<p>Alzheimer’s disease (AD) is the most common cause of dementia in the aged population. Histone acetylation is a major epigenetic mechanism linked to memory formation and cognitive function. Histone deacetylases (HDACs) are responsible for the deacetylation of lysine residues in histone proteins. Although pan-HDAC inhibitors are effective in ameliorating AD phenotypes in preclinical models, they are associated with potential unfavorable adverse effects and barely translated into clinical trials. Therefore, the development of novel HDAC inhibitors with a well isoform-selectivity has been desired in AD drug discovery. Among various HDAC isoforms, HDAC3 is highly expressed in neurons and exhibits detrimental effects on synaptic plasticity and cognitive function. Moreover, HDAC3 provokes neuroinflammation and neurotoxicity and contributes to AD pathogenesis. In this review, we highlight HDAC3 as an attractive therapeutic target for disease-modifying therapy in AD. In addition, we discuss the therapeutic potential of HDAC3 inhibitors in other neurological disorders.</p>

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HDAC3 as an Emerging Therapeutic Target for Alzheimer's Disease and other Neurological Disorders

  • 期刊论文

  • 发表日期：

    2025年3月24日

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  • Yonghe Li,
  • Taha Izhar,
  • Takahisa Kanekiyo

摘要

Alzheimer’s disease (AD) is the most common cause of dementia in the aged population. Histone acetylation is a major epigenetic mechanism linked to memory formation and cognitive function. Histone deacetylases (HDACs) are responsible for the deacetylation of lysine residues in histone proteins. Although pan-HDAC inhibitors are effective in ameliorating AD phenotypes in preclinical models, they are associated with potential unfavorable adverse effects and barely translated into clinical trials. Therefore, the development of novel HDAC inhibitors with a well isoform-selectivity has been desired in AD drug discovery. Among various HDAC isoforms, HDAC3 is highly expressed in neurons and exhibits detrimental effects on synaptic plasticity and cognitive function. Moreover, HDAC3 provokes neuroinflammation and neurotoxicity and contributes to AD pathogenesis. In this review, we highlight HDAC3 as an attractive therapeutic target for disease-modifying therapy in AD. In addition, we discuss the therapeutic potential of HDAC3 inhibitors in other neurological disorders.